The purpose of this application is to establish a clinical research center for the neuropsychoendocrinological study of the major mental disorders of adults and children which form the hard core of mental health problems. In adults these include depression, mania, alcoholism, schizophrenia and the mental syndromes associated with renal dialysis; in children, hyperkinesis, autism, and mental retardation. The theoretical base for these studies consists of the principles of neuroendocrinology and the principles of neurotransmitter physiology. A pituitary response fault (diminished TSH response to TRH) has been identified in some depressed patients and in some alcoholic patients. Follow-up studies will be performed to ascertain whether in these conditions the fault is related to the state of illness or to the trait of being at high risk for these illnesses. Parallel pituitary response testing, with TRH, will be carried out in psychotic and hyperkinetic children. Related neuroendocrine investgations will be addressed to renal dialysis patients who show characteristic mental syndromes. In adult schizophrenic patients we will explore relationships between the hypothalamic-pituitary-thyroid axis and the hypothalamic-pituitary-adrenal axis. Studies already performed show that in schizophrenia there is dissociation between these axes; TSH response appears to be positively related to baseline cortisol values. In normal controls and in all other diagnostic groups the relationship is negative. The altered relationships may provide a biochemical marker for schizophrenia. The techniques of modern genetics will be used to explore relationships between affective disorders and alcoholism and between alcoholism and hyperkinetic syndrome. When probands show TSH blunting relatives will be tested to establish whether the physiological fault is a marker in families for the demonstration of illness. Four disciplines of basic science will be brought to bear on problems relevant to clinical goals. These are biochemistry, animal neuroendocrinology, animal psychopharmacology, and peptide behavioral pharmacology. While work in these areas is expected to clarify problems of clinical origin, it is also expected to provide findings that will suggest clinical intervention. The nexus of related clinical and basic projects provide a basis for rich training and practical experiences for several categories of trainees.